Preeclampsia is a life-threatening complication of pregnancy affecting maternal and fetal health of millions worldwide. Consequences of preeclampsia include both short- and long-term adverse health effects for both the mother and her baby. Despite decades of research providing evidence of a strong heritability component, specific genetic contributions have yet to be identified. A critical barrier to our understanding o the genetics of preeclampsia has been a nearly exclusive focus on maternal genetic contributions. The fetus is now known to be an active participant in pregnancy, and the central role of the placenta in the pathogenesis of preeclampsia implies that the fetus is likely to play a pivotal role in the disease process. The broad long-term goal of this research is to advance substantially our current and limited understanding of the genetic etiology of preeclampsia. Utilizing existing DNA from a previous case-control study of preeclampsia, together with genotyping data available in dbGAP on mother-baby pairs who have been similarly characterized on case and control status, we propose to build upon a preliminary genome-wide study of maternal genetic contributions to preeclampsia; this will be among the first studies to specifically examine fetal genetic contributions to preeclampsia and explore joint maternal-fetal gene effects. Utilizing contemporary, methodologically rigorous approaches, we will address the following specific aims: Aim 1: Develop a Pathway Analysis database for preeclampsia incorporating genetic information from published literature, expression databases, and biological pathways to identify an informative set of candidate fetal SNPs or CNVs for association studies of preeclampsia; Aim 2: To identify distinct fetal genetic variants associated with the maternal syndrome of preeclampsia. As a secondary aim, we propose to explore methodologies for identifying joint maternal-fetal genetic effects. The proposed research will develop and advance our understanding of the genetics of preeclampsia by studying the fetal contributions to preeclampsia using a combined genome-wide and candidate gene approach. In addition, we will explore individual and joint contributions of both maternal and fetal genotypes. Identifying distinct fetal genetic contributions to preeclampsia will inform biological understanding of the disease process, and could have a major impact on clinical practice by enabling early identification of at-risk pregnancies defined by fetal and maternal genetics. The data from this R21 will provide pilot data to inform development of an R01 to extend the findings of this study and to target and confirm the biological basis for genetic variants through placental expression studies and re-sequencing of relevant genes. The proposed research has tremendous potential to impact knowledge and practice in this area with its pioneering emphasis on fetal genetics and a carefully planned, interdisciplinary and integrated phased approach using state-of-the-art methodologies from the fields of statistical genetics, epidemiology, and clinical medicine. PUBLIC HEALTH RELEVANCE: The proposed research will advance our understanding of the genetics of preeclampsia by studying contributions of biologically relevant fetal genetic variants identified using a hybrid analytical approach that combines a comprehensive bioinformatics approach with a hypothesis- free genome wide association approach. Identifying distinct fetal genetic contributions to preeclampsia will inform our biological understanding of the disease, and could have a major impact on clinical practice by identifying novel targets for therapies for preeclampsia (including pharmacological and non-pharmacological treatments targeted at identified proteins, and enabling early identification of at-risk pregnancies.